Unexplained iron deficiency anemia: does Helicobacter pylori have a role to play?

Unexplained iron deficiency anemia: does Helicobacter pylori have a role to play? Abstract Background and aim Testing for Helicobacter pylori (Hp) infection is recommended for work-up of unexplained iron deficiency anemia (IDA), although the evidence supporting this recommendation is scant. The aim of this study was to investigate the association between Hp infection and unexplained iron deficiency (ID) or IDA in the older adult population without significant upper gastrointestinal source of blood loss. Methods Retrospective single-center cohort study; 523 out of 1253 consecutive patients who underwent esophagogastroduodenoscopy with no significant upper and/or lower gastrointestinal source for blood loss or risk factors for IDA. Comparisons were made between the Hp-positive and Hp-negative groups using Fisher exact test, chi-square test and Student’s t-test. Univariate and multiple logistic regression analyses were used to identify significant risk factors associated with ID and IDA. Results One hundred and three subjects (19.7%) had Hp infection and 420 (80.3%) were negative for Hp. Sixty-eight (22.1%) out of 307 subjects with available serum iron profile had unexplained ID and 28 (5.4%) out of 510 subjects with available hemoglobin profile had unexplained IDA. No association was found between ID/IDA and Hp infection in univariate and multiple logistic regression analyses. Conclusion We found no association between unexplained ID or IDA and Hp infection in older adult population without peptic ulcer disease or significant upper gastrointestinal source of blood loss. Helicobacter pylori, anemia, iron deficiency Introduction Helicobacter pylori (Hp) is the most common chronic bacterial infection in humans [1,2]. Iron deficiency anemia (IDA) is also a common condition with a prevalence of 1–2% of the adult population in the USA [3] and up to 16.6% in older adults [4]. More recent reports suggest a variable and higher prevalence of anemia in older adults, ranging between 2.9% and 61%, depending on the population studied and definition of anemia [5]. The major cause of iron deficiency (ID) in developed countries is overt or occult gastrointestinal blood loss [6]. Existing practice guidelines support the practice of performing upper and lower gastrointestinal endoscopic evaluation in patients with IDA and wireless video capsule endoscopy in those with unrevealing bidirectional endoscopic evaluation [7]. Despite these diagnostic modalities, the etiology of obscure gastrointestinal bleeding may remain elusive in approximately 30% of the patients [8]. Peptic ulcer disease caused by Hp infection can lead to gastrointestinal blood loss and IDA. Whether Hp infection can lead to IDA in the absence of peptic ulcer disease is controversial. Most of the data supporting association of Hp infection and IDA come from clinical studies conducted in children and pre-menopausal women with a relatively high iron requirement [9–11] and in those living in areas with a high prevalence for Hp infection [12]. The majority of the epidemiological studies that support this association have used serologic tests that do not necessarily diagnose active Hp infection. In addition, most of these studies have not ruled out the major causes of IDA such as peptic ulcer disease by esophagogastroduodenoscopy (EGD) [13]. Thus, the applicability of the available study findings in adult population living in areas with low prevalence for Hp infection who are not vulnerable to ID is controversial. The available data supporting association between Hp infection and ID do not prove cause and effect [14]. Nevertheless, the Maastricht IV Consensus on the management of Hp infection recommends testing and treatment for Hp infection in patients with unexplained IDA [15]. Hence our study was performed to evaluate the association between Hp infection and unexplained IDA in adult patients without obvious risk factors for ID living in areas with low prevalence for Hp infection. Methods Patients The study involved collection of Hp infection data on 1253 consecutive patients undergoing diagnostic or therapeutic upper gastrointestinal endoscopy at the Veterans Affairs Medical Center, Syracuse, from 1 January 1998 to 28 April 2004. All patients underwent EGD with Hp testing by standard biopsy protocol (two antral and two gastric body biopsies) as part of a previous Institutional Review Board-approved study investigating new diagnostic tests and treatment protocols for Hp infection [16,17]. One biopsy each from the antrum and body was sent for histology and rapid urease testing/Campylobacter-like organism (CLO) test. A subgroup of these patients (from 1 January 1998 to 31 December 1999) had consented to collection and storage of fasting serum samples prior to endoscopy. Serum iron tests were performed on these samples. A review of medical records was performed in all the subjects to determine the presence of ID/IDA. Medical, laboratory and pharmacy electronic records from 6 months before to 6 months after the performance of the endoscopy were reviewed. Demographic and clinical data included history of medical conditions known to cause ID, obvious causes for acute and/or chronic blood loss or impaired iron absorption, prior gastrointestinal surgery, alcohol or drug abuse, prescription/over-the-counter medication use (non-steroidal anti-inflammatory, proton pump inhibitor, iron supplementation, anticoagulant and antiplatelet medications), pertinent laboratory results, endoscopy and pathology reports. Patients with significant source of chronic and/or acute gastrointestinal blood loss identified on upper endoscopy and/or lower endoscopy [18,19], abnormal small bowel biopsies, clinical diagnosis consistent with celiac disease or other malabsorption syndromes, obvious cause of non-GI blood loss such as epistaxis or heavy menstrual bleed, previous treatment for Hp, indeterminate Hp status, ongoing iron therapy and insufficient clinical data were excluded. Determination of Hp status Hp status was determined by CLO test and presence of Hp organisms on histological evaluation of gastric biopsies. Positive Hp status was defined as positive CLO test and presence of Hp on histology. Negative Hp status was defined as negative CLO test and absence of Hp on histology. In patients with discordant results by CLO and histology, positive Hp serology or presence of chronic active gastritis on biopsy was used to determine the presence of active Hp infection. Patients with discordant CLO/histology results, who were on proton pump inhibitors (PPIs) and had no serology tests were deemed indeterminate. Determination of ID and IDA Blood hemoglobin level of <13 and <12 g/dL in men and women respectively was used to define anemia [20]. Patients were considered iron-deficient if serum ferritin level was <41 ng/mL. Prior studies conducted in anemic patients have shown that a cutoff serum ferritin level of 41 ng/mL has a sensitivity and specificity of 98% [21,22]. In those with anemia, we also used a higher cutoff ferritin level of 100 ng/mL [23] to ensure capture of ID in those with potentially coexistent anemia of chronic disease. Statistical analysis Demographic data, clinical characteristics and laboratory parameters including serum iron results were compared in the Hp-positive and Hp-negative groups. Fisher exact test or chi-square test was employed for analysis of categorical variables and Student’s t-test was used for analysis of continuous variables. A probability value of <0.05 was considered statistically significant. Similar univariate analysis of demographic data, clinical characteristics, Hp status and medication use [non-steroidal anti-inflammatory drugs (NSAIDs) and PPIs] was also performed in the groups with ID and IDA. Multiple logistic regression analysis was then performed using variables that were statistically significant on univariate analysis in the groups with ID and IDA. Results A total of 1253 consecutive patients who underwent EGD and standard testing for Hp infection from 1 January 1998 to 28 April 2004 were eligible for inclusion in the study. Seven hundred and 30 patients were excluded [endoscopic identification of a significant gastrointestinal bleeding source (n = 557), other causes for ID including celiac disease (n=60), inadequate data (n=74), previous treatment for Hp (n=27) and indeterminate Hp infection status (n=12)]. The final study population consisted of 523 subjects, of whom 488 (93.3%) were males and 35 (6.7%) were females. All the patients underwent EGD and 72% (n=378) underwent flexible sigmoidoscopy or colonoscopy. Out of the 523 subjects, 103 had Hp infection (19.7%) and 420 were negative for Hp (80.3%) (Table 1). The female patients were relatively younger as compared to the males (mean age 51.9 vs 61.8 years, data not shown). Age, gender, race, mean ferritin level, hemoglobin level or ID was not associated with Hp infection. Table 1. Comparison of variables in 523 patients with and without Helicobacter pylori (Hp) infection Hp-positive (n=103) Hp-negative (n=420) p-value Odds ratio 95% confidence interval Gender 0.66 0.82 0.36–1.85  Male 95 (19.5) 393 (80.5)  Female 8 (22.9) 27 (77.1) Race 0.24  Caucasian 93 (19.0) 396 (81.0)  African American 14 (63.6)  Others 2 (16.7) 10 (83.3) Age, years 61.7 ± 11.7 61.0 ± 13.1 0.62 Hemoglobin, g/dL 14.3 ± 1.8 (n=102) 14.1 ± 1.9 (n=408) 0.27 Ferritin, ng/mL 174.1 ± 215.0 (n=71) 185.1 ± 251.6 (n=236) 0.74 Iron deficiency 12 (17.6) 56 (82.4) 0.26 0.65 0.33–1.30 Hp-positive (n=103) Hp-negative (n=420) p-value Odds ratio 95% confidence interval Gender 0.66 0.82 0.36–1.85  Male 95 (19.5) 393 (80.5)  Female 8 (22.9) 27 (77.1) Race 0.24  Caucasian 93 (19.0) 396 (81.0)  African American 14 (63.6)  Others 2 (16.7) 10 (83.3) Age, years 61.7 ± 11.7 61.0 ± 13.1 0.62 Hemoglobin, g/dL 14.3 ± 1.8 (n=102) 14.1 ± 1.9 (n=408) 0.27 Ferritin, ng/mL 174.1 ± 215.0 (n=71) 185.1 ± 251.6 (n=236) 0.74 Iron deficiency 12 (17.6) 56 (82.4) 0.26 0.65 0.33–1.30 Data are presented as mean ± standard deviation or number (percentage). Table 1. Comparison of variables in 523 patients with and without Helicobacter pylori (Hp) infection Hp-positive (n=103) Hp-negative (n=420) p-value Odds ratio 95% confidence interval Gender 0.66 0.82 0.36–1.85  Male 95 (19.5) 393 (80.5)  Female 8 (22.9) 27 (77.1) Race 0.24  Caucasian 93 (19.0) 396 (81.0)  African American 14 (63.6)  Others 2 (16.7) 10 (83.3) Age, years 61.7 ± 11.7 61.0 ± 13.1 0.62 Hemoglobin, g/dL 14.3 ± 1.8 (n=102) 14.1 ± 1.9 (n=408) 0.27 Ferritin, ng/mL 174.1 ± 215.0 (n=71) 185.1 ± 251.6 (n=236) 0.74 Iron deficiency 12 (17.6) 56 (82.4) 0.26 0.65 0.33–1.30 Hp-positive (n=103) Hp-negative (n=420) p-value Odds ratio 95% confidence interval Gender 0.66 0.82 0.36–1.85  Male 95 (19.5) 393 (80.5)  Female 8 (22.9) 27 (77.1) Race 0.24  Caucasian 93 (19.0) 396 (81.0)  African American 14 (63.6)  Others 2 (16.7) 10 (83.3) Age, years 61.7 ± 11.7 61.0 ± 13.1 0.62 Hemoglobin, g/dL 14.3 ± 1.8 (n=102) 14.1 ± 1.9 (n=408) 0.27 Ferritin, ng/mL 174.1 ± 215.0 (n=71) 185.1 ± 251.6 (n=236) 0.74 Iron deficiency 12 (17.6) 56 (82.4) 0.26 0.65 0.33–1.30 Data are presented as mean ± standard deviation or number (percentage). Out of the 307 subjects with available serum ferritin results, 68 subjects (22.1%) were iron-deficient and 239 subjects had no ID (Table 2). Female gender was significantly associated with ID on univariate as well as multiple regression analysis (48% vs 20%, p = 0.004). Other variables such as Hp infection, age, gender, race, PPI use or NSAID use were not associated with ID. Table 2. Comparison of variables in patients with and without iron deficiency (serum ferritin results available in 307 patients) ID-positive (n=68) ID-negative (n=239) p-value Odds ratio 95% confidence interval Hp infection 12 (16.9) 59 (83.1) 0.26 0.65 0.33–1.30 Gender 0.004 0.27 0.12–0.62  Male 56 (19.9) 226 (80.1)  Female 12 (48.0) 13 (52.0) Race 0.48  Caucasian 65 (23) 218 (77)  African American 3 (18.8) 13 (81.2)  Others 0 (0.0) 8 (100.0) NSAID use 36 (22.2) 126 (77.8) 0.99 1.01 0.59–1.75 PPI use 27 (20.3) 106 (79.7) 0.58 0.83 0.48–1.43 Age, years 62.3 ± 12.7 61.9 ± 13.2 0.81 ID-positive (n=68) ID-negative (n=239) p-value Odds ratio 95% confidence interval Hp infection 12 (16.9) 59 (83.1) 0.26 0.65 0.33–1.30 Gender 0.004 0.27 0.12–0.62  Male 56 (19.9) 226 (80.1)  Female 12 (48.0) 13 (52.0) Race 0.48  Caucasian 65 (23) 218 (77)  African American 3 (18.8) 13 (81.2)  Others 0 (0.0) 8 (100.0) NSAID use 36 (22.2) 126 (77.8) 0.99 1.01 0.59–1.75 PPI use 27 (20.3) 106 (79.7) 0.58 0.83 0.48–1.43 Age, years 62.3 ± 12.7 61.9 ± 13.2 0.81 Data are presented as mean ± standard deviation or number (percentage). ID, iron deficiency; Hp, Helicobacter pylori; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor. Table 2. Comparison of variables in patients with and without iron deficiency (serum ferritin results available in 307 patients) ID-positive (n=68) ID-negative (n=239) p-value Odds ratio 95% confidence interval Hp infection 12 (16.9) 59 (83.1) 0.26 0.65 0.33–1.30 Gender 0.004 0.27 0.12–0.62  Male 56 (19.9) 226 (80.1)  Female 12 (48.0) 13 (52.0) Race 0.48  Caucasian 65 (23) 218 (77)  African American 3 (18.8) 13 (81.2)  Others 0 (0.0) 8 (100.0) NSAID use 36 (22.2) 126 (77.8) 0.99 1.01 0.59–1.75 PPI use 27 (20.3) 106 (79.7) 0.58 0.83 0.48–1.43 Age, years 62.3 ± 12.7 61.9 ± 13.2 0.81 ID-positive (n=68) ID-negative (n=239) p-value Odds ratio 95% confidence interval Hp infection 12 (16.9) 59 (83.1) 0.26 0.65 0.33–1.30 Gender 0.004 0.27 0.12–0.62  Male 56 (19.9) 226 (80.1)  Female 12 (48.0) 13 (52.0) Race 0.48  Caucasian 65 (23) 218 (77)  African American 3 (18.8) 13 (81.2)  Others 0 (0.0) 8 (100.0) NSAID use 36 (22.2) 126 (77.8) 0.99 1.01 0.59–1.75 PPI use 27 (20.3) 106 (79.7) 0.58 0.83 0.48–1.43 Age, years 62.3 ± 12.7 61.9 ± 13.2 0.81 Data are presented as mean ± standard deviation or number (percentage). ID, iron deficiency; Hp, Helicobacter pylori; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor. Out of the total of 523 subjects, 510 subjects had hemoglobin levels available and they were classified as anemic and not anemic. IDA was present in 28 (5.4%) with available ferritin results, when a cutoff of <41 ng/mL was used for serum ferritin level to define ID (Table 3). Using a higher cutoff for serum ferritin level of <100 ng/mL in those with anemia, IDA was present in only 46 subjects (9.0%). No significant association between IDA and Hp infection was found even with using a higher cutoff for serum ferritin level of <100 ng/mL in those with anemia (data not shown). However, the patients in this subgroup with IDA and higher serum ferritin cutoff were found to be significantly older compared to those without IDA (mean age, 66.04 vs 60.71 years, p < 0.01) (data not shown). Table 3. Comparison of variables in patients with and without iron deficiency anemia (hemoglobin levels available in only 510 patients) IDA-positive (n=28) IDA-negative (n=482) p-value Odds ratio 95% confidence interval Hp infection 4 (3.9) 98 (96.1) 0.63 0.65 0.22–1.93 Gender 0.43 0.59 0.17–2.07  Male 25 (5.3) 450 (94.7)  Female 3 (8.6) 32 (91.4) Race 0.76  Caucasian 26 (5.5) 450 (94.5)  African American 2 (9.1) 20 (90.9)  Others 0 (0.0) 11 (100.0) NSAID use 15 (5.7) 250 (94.3) 0.84 1.12 0.51–2.44 PPI use 11 (4.4) 239 (95.6) 0.33 0.66 0.30–1.43 Age, years 65.4 ± 12.2 61 ± 12.8 0.07 IDA-positive (n=28) IDA-negative (n=482) p-value Odds ratio 95% confidence interval Hp infection 4 (3.9) 98 (96.1) 0.63 0.65 0.22–1.93 Gender 0.43 0.59 0.17–2.07  Male 25 (5.3) 450 (94.7)  Female 3 (8.6) 32 (91.4) Race 0.76  Caucasian 26 (5.5) 450 (94.5)  African American 2 (9.1) 20 (90.9)  Others 0 (0.0) 11 (100.0) NSAID use 15 (5.7) 250 (94.3) 0.84 1.12 0.51–2.44 PPI use 11 (4.4) 239 (95.6) 0.33 0.66 0.30–1.43 Age, years 65.4 ± 12.2 61 ± 12.8 0.07 Data are presented as mean ± standard deviation or number (percentage). IDA, iron deficiency anemia; Hp, Helicobacter pylori; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor. Table 3. Comparison of variables in patients with and without iron deficiency anemia (hemoglobin levels available in only 510 patients) IDA-positive (n=28) IDA-negative (n=482) p-value Odds ratio 95% confidence interval Hp infection 4 (3.9) 98 (96.1) 0.63 0.65 0.22–1.93 Gender 0.43 0.59 0.17–2.07  Male 25 (5.3) 450 (94.7)  Female 3 (8.6) 32 (91.4) Race 0.76  Caucasian 26 (5.5) 450 (94.5)  African American 2 (9.1) 20 (90.9)  Others 0 (0.0) 11 (100.0) NSAID use 15 (5.7) 250 (94.3) 0.84 1.12 0.51–2.44 PPI use 11 (4.4) 239 (95.6) 0.33 0.66 0.30–1.43 Age, years 65.4 ± 12.2 61 ± 12.8 0.07 IDA-positive (n=28) IDA-negative (n=482) p-value Odds ratio 95% confidence interval Hp infection 4 (3.9) 98 (96.1) 0.63 0.65 0.22–1.93 Gender 0.43 0.59 0.17–2.07  Male 25 (5.3) 450 (94.7)  Female 3 (8.6) 32 (91.4) Race 0.76  Caucasian 26 (5.5) 450 (94.5)  African American 2 (9.1) 20 (90.9)  Others 0 (0.0) 11 (100.0) NSAID use 15 (5.7) 250 (94.3) 0.84 1.12 0.51–2.44 PPI use 11 (4.4) 239 (95.6) 0.33 0.66 0.30–1.43 Age, years 65.4 ± 12.2 61 ± 12.8 0.07 Data are presented as mean ± standard deviation or number (percentage). IDA, iron deficiency anemia; Hp, Helicobacter pylori; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor. Logistic regression analysis showed female gender to be the only significant factor associated with ID (Table 4). The significance of gender however did not hold true in those with IDA on univariate or multivariate analysis (data not shown). Table 4. Logistic regression model in subjects with iron deficiency p-value Odds ratio 95% confidence interval Age (years) 0.57 1.01 0.98–1.03 Hp infection (positive vs negative) 0.16 0.59 0.28–1.23 Gender (male vs female) <0.001 0.21 0.09–0.52 Race (Caucasian vs others) 0.20 2.34 0.63–8.64 NSAID Uses (yes vs no) 0.59 1.17 0.66–2.08 PPI use (yes vs no) 0.47 0.81 0.45–1.45 p-value Odds ratio 95% confidence interval Age (years) 0.57 1.01 0.98–1.03 Hp infection (positive vs negative) 0.16 0.59 0.28–1.23 Gender (male vs female) <0.001 0.21 0.09–0.52 Race (Caucasian vs others) 0.20 2.34 0.63–8.64 NSAID Uses (yes vs no) 0.59 1.17 0.66–2.08 PPI use (yes vs no) 0.47 0.81 0.45–1.45 Hp, Helicobacter pylori; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor. Table 4. Logistic regression model in subjects with iron deficiency p-value Odds ratio 95% confidence interval Age (years) 0.57 1.01 0.98–1.03 Hp infection (positive vs negative) 0.16 0.59 0.28–1.23 Gender (male vs female) <0.001 0.21 0.09–0.52 Race (Caucasian vs others) 0.20 2.34 0.63–8.64 NSAID Uses (yes vs no) 0.59 1.17 0.66–2.08 PPI use (yes vs no) 0.47 0.81 0.45–1.45 p-value Odds ratio 95% confidence interval Age (years) 0.57 1.01 0.98–1.03 Hp infection (positive vs negative) 0.16 0.59 0.28–1.23 Gender (male vs female) <0.001 0.21 0.09–0.52 Race (Caucasian vs others) 0.20 2.34 0.63–8.64 NSAID Uses (yes vs no) 0.59 1.17 0.66–2.08 PPI use (yes vs no) 0.47 0.81 0.45–1.45 Hp, Helicobacter pylori; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor. Discussion Our study did not show an association between ID/IDA and Hp infection in adult population, using strict (ferritin level of <41ng/mL) and liberal (ferritin level of <100 ng/mL) criteria to define ID/IDA. This lack of association may be attributed to the low vulnerability of our patients to ID/IDA (predominantly adult males with no increased risk for ID living in areas with low prevalence for Hp infection) as well as the exclusion of upper and/or lower gastrointestinal source of blood loss and confirmation of the presence of active Hp infection. The prevalence of Hp infection in our study population was 19.7% compared to 30.1–39.5% in other epidemiologic studies performed in the USA [13]. This lower prevalence is likely explained by the use of serology for detecting Hp infection in the above studies and the exclusion of patients with indeterminate Hp infection status, previous treatment for Hp infection, and upper and/or lower gastrointestinal source of blood loss in our study. Although female gender was the only significant factor associated with ID in multiple logistic regression, there was no significant difference in the Hp infection status in females with and without ID. However, the small number of female patients in our study (6.7%) limits further interpretation. The mechanisms by which Hp infection is postulated to cause IDA are Hp-associated chronic gastritis resulting in hypo- or achlorhydria, reduced ascorbic acid secretion and reduced intestinal iron absorption, occult blood loss due to chronic erosive gastritis, and sequestration and utilization of iron by Hp [24]. The major studies that have reported Hp infection to be an independent risk factor for IDA in North America were conducted in school-aged children residing in rural Alaska with a high prevalence of Hp infection and IDA [12] and in participants of the National Health and Nutrition Examination Survey in whom serologic tests were used for diagnosis of Hp infection [13]. Other studies that suggested a role for Hp eradication in improving IDA were conducted in children, adolescents and pre-menopausal women who have a relatively high iron requirement to meet the demands of growth and menstrual blood loss [9–11]. On the other hand, there are epidemiologic studies that showed no association between Hp seropositivity and ID/IDA [25–29]. In summary, the causal relationship between Hp infection and ID/IDA remains controversial. Our study did not show any association between Hp infection and ID/IDA. The Maastricht IV Consensus on the management of Hp infection recommends testing and treatment of Hp infection in patients with unexplained IDA [15]. Although these guidelines may be applicable in countries with high prevalence for Hp infection, the universal adoption of this guideline in areas with low prevalence for Hp infection such as the USA may result in unnecessary testing and treatment. More importantly, this practice could delay the diagnosis of other serious conditions that could cause ID/IDA in older population. The evidence that carriage of certain Hp strains is inversely related to the prevalence of Barrett’s esophagus, esophageal adenocarcinoma, asthma and atopic disorders has prompted some authors to warn against testing and treating for Hp infection in asymptomatic individuals [30]. While we concur with the current guidelines that, if testing for Hp infection is undertaken, appropriate treatment and confirmation of eradication of the infection should be ensured in all patients with positive test result for Hp infection, our study results do not support the recommendation that testing for Hp infection should be performed in all patients with unexplained IDA. The strengths of our study include the identification and exclusion of significant upper gastrointestinal source of blood loss via EGD in all the subjects, the adoption of strict criteria to determine active Hp infection and the use of a higher cutoff for serum ferritin to capture those with potential ID. In most of the observational epidemiologic studies evaluating association between Hp infection and ID, EGD was not performed [12,13,25–27,31–40]. We used a combination of CLO testing and detection of Hp on histology to adjudicate Hp status, which provides a more accurate determination of the Hp infection status. The majority of previous studies looking at association of Hp and IDA used serology for identification of Hp infection [13,26,27,31–38]. Only a few studies used tests besides serology to determine active Hp infection [12,39–42]. However, these studies were conducted in subjects vulnerable to ID such as children and adolescent females living in areas with a high prevalence for Hp infection. The limitations of our study include the retrospective study design, the study population comprising predominantly adult males who are typically not vulnerable to ID and the availability of lower gastrointestinal endoscopy results in only 72% of the study population. The selection of a homogenous patient population without the confounding effects of vulnerability to ID is, however, a better model to study the association between Hp infection and IDA. Although the study was retrospective in nature, a large number of our patients had biopsies for Hp performed by protocol and serum samples collected for calculation of serum iron indices prospectively at the time of EGD. While the availability of lower gastrointestinal endoscopy results on all patients would have been ideal, bidirectional endoscopy as well as appropriate small bowel imaging studies was conducted in all the patients who presented with overt or occult gastrointestinal blood loss. Additionally, all patients with a significant source of chronic and/or acute gastrointestinal blood loss identified on endoscopic or small bowel imaging tests were excluded from the study. It is to be also noted that prior studies showing association between unexplained ID and Hp infection did not have strict exclusion criteria as are used in our study and did not have upper and lower gastrointestinal endoscopy data on all patients. In conclusion, we found no association between ID or IDA and Hp infection in older adult population without peptic ulcer disease or significant upper gastrointestinal source of blood loss. Our study does not support routine testing for Hp infection in adult patients with unexplained IDA living in areas with low prevalence for Hp infection. More importantly, work-up of IDA, particularly in patients above 60 years of age, should not end with the diagnosis of Hp infection, as such a practice could lead to delayed diagnosis of potentially more serious underlying pathology. Conflict of interest statement: none declared. References 1 Cave DR. Transmission and epidemiology of Helicobacter pylori . Am J Med 1996 ; 100(Suppl 5A) : 12S – 18S . Google Scholar CrossRef Search ADS 2 Pounder RE , Ng D. The prevalence of Helicobacter pylori infection in different countries . Aliment Pharmacol Ther 1995 ; 9(Suppl 2) : 33 – 9 . Google Scholar PubMed 3 Looker AC , Dallman PR , Carroll MD et al. Prevalence of iron deficiency in the United States . JAMA 1997 ; 277 : 973 – 6 . Google Scholar CrossRef Search ADS PubMed 4 Guralnik JM , Eisenstaedt RS , Ferrucci L et al. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia . Blood 2004 ; 104 : 2263 – 8 . Google Scholar CrossRef Search ADS PubMed 5 Beghe C, , Wilson A , Ershler WB. Prevalence and outcomes of anemia in geriatrics: a systematic review of the literature . Am J Med 2004 ; 116(Suppl 7A) : 3S – 10S . Google Scholar CrossRef Search ADS PubMed 6 Cook JD , Skikne BS. Iron deficiency: definition and diagnosis . J Intern Med 1989 ; 226 : 349 – 55 . Google Scholar CrossRef Search ADS PubMed 7 Raju GS , Gerson L , Das A et al. ; American Gastroenterological Association. American Gastroenterological Association (AGA) Institute technical review on obscure gastrointestinal bleeding . Gastroenterology 2007 ; 133 : 1697 – 717 . Google Scholar CrossRef Search ADS PubMed 8 Szold A , Katz LB , Lewis BS. Surgical approach to occult gastrointestinal bleeding . Am J Surg 1992 ; 163 : 90 – 3 . Google Scholar CrossRef Search ADS PubMed 9 Annibale B , Marignani M , Monarca B et al. Reversal of iron deficiency anemia after Helicobacter pylori eradication in patients with asymptomatic gastritis . Ann Intern Med 1999 ; 131 : 668 – 72 . Google Scholar CrossRef Search ADS PubMed 10 Choe YH , Kim SK , Son BK et al. Randomized placebo-controlled trial of Helicobacter pylori eradication for iron-deficiency anemia in preadolescent children and adolescents . Helicobacter 1999 ; 4 : 135 – 9 . Google Scholar CrossRef Search ADS PubMed 11 Hacihanefioglu A , Edebali F , Celebi A et al. Improvement of complete blood count in patients with iron deficiency anemia and Helicobacter pylori infection after the eradication of Helicobacter pylori . Hepatogastroenterology 2004 ; 51 : 313 – 5 . Google Scholar PubMed 12 Baggett HC , Parkinson AJ , Muth PT et al. Endemic iron deficiency associated with Helicobacter pylori infection among school-aged children in Alaska . Pediatrics 2006 ; 117 : e396 – 404 . Google Scholar CrossRef Search ADS PubMed 13 Cardenas VM , Mulla ZD , Ortiz M et al. Iron deficiency and Helicobacter pylori infection in the United States . Am J Epidemiol 2006 ; 163 : 127 – 34 . Google Scholar CrossRef Search ADS PubMed 14 Chey WD , Wong BC ; Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection . Am J Gastroenterol 2007 ; 102 : 1808 – 25 . Google Scholar CrossRef Search ADS PubMed 15 Malfertheiner P , Megraud F , O’Morain CA et al. Management of Helicobacter pylori infection—the Maastricht IV/ Florence Consensus Report . Gut 2012 ; 61 : 646 – 64 . Google Scholar CrossRef Search ADS PubMed 16 Ahmed F , Murthy UK , Chey WD et al. Evaluation of the Ez-HBT Helicobacter blood test to establish Helicobacter pylori eradication . Aliment Pharmacol Ther 2005 ; 22 : 875 – 80 . Google Scholar CrossRef Search ADS PubMed 17 Chey WD , Murthy U , Toskes P et al. The 13C-urea blood test accurately detects active Helicobacter pylori infection: a United States, multicenter trial . Am J Gastroenterol 1999 ; 94 : 1522 – 4 . Google Scholar CrossRef Search ADS PubMed 18 Rockey DC , Cello JP. Evaluation of the gastrointestinal tract in patients with iron-deficiency anemia . N Engl J Med 1993 ; 329 : 1691 – 5 . Google Scholar CrossRef Search ADS PubMed 19 Zuckerman GR , Prakash C , Askin MP et al. AGA technical review on the evaluation and management of occult and obscure gastrointestinal bleeding . Gastroenterology 2000 ; 118 : 201 – 21 . Google Scholar CrossRef Search ADS PubMed 20 Nutritional anaemias . Report of a WHO scientific group . World Health Organ Tech Rep Ser 1968 ; 405 : 5 – 37 . PubMed 21 Mast AE , Blinder MA , Gronowski AM et al. Clinical utility of the soluble transferrin receptor and comparison with serum ferritin in several populations . Clin Chem 1998 ; 44 : 45 – 51 . Google Scholar PubMed 22 Punnonen K , Irjala K , Rajamaki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency . Blood 1997 ; 89 : 1052 – 7 . Google Scholar PubMed 23 Guyatt GH , Oxman AD , Ali M et al. Laboratory diagnosis of iron-deficiency anemia: an overview . J Gen Inten Med 1992 ; 7 : 145 – 53 . Google Scholar CrossRef Search ADS 24 DuBois S , Kearney DJ. Iron-deficiency anemia and Helicobacter pylori infection: a review of the evidence . Am J Gastroenterol 2005 ; 100 : 453 – 9 . Google Scholar CrossRef Search ADS PubMed 25 Collett JA , Burt MJ , Frampton CM et al. Seroprevalence of Helicobacter pylori in the adult population of Christchurch: risk factors and relationship to dyspeptic symptoms and iron studies . N Z Med J 1999 ; 112 : 292 – 5 . Google Scholar PubMed 26 Choi JW. Does Helicobacter pylori infection relate to iron deficiency anaemia in prepubescent children under 12 years of age? Acta Paediatr 2003 ; 92 : 970 – 2 . Google Scholar CrossRef Search ADS PubMed 27 Pilott A , Fabrello R , Franceschi M et al. Helicobacter pylori infection in asymptomatic elderly subjects living at home or in a nursing home: effects on gastric function and nutritional status . Age Ageing 1996 ; 25 : 245 – 9 . Google Scholar CrossRef Search ADS PubMed 28 Gessner BD , Baggett HC , Muth PT et al. A controlled, household-randomized, open-label trial of the effect that treatment of Helicobacter pylori infection has on iron deficiency in children in rural Alaska . J Infect Dis 2006 ; 193 : 537 – 46 . Google Scholar CrossRef Search ADS PubMed 29 Fagan RP , Dunaway CE , Bruden DL et al. Controlled, household-randomized, open-label trial of the effect of treatment of Helicobacter pylori infection on iron deficiency among children in rural Alaska: results at 40 months . J Infect Dis 2009 ; 199 : 652 – 60 . Google Scholar CrossRef Search ADS PubMed 30 Polk DB , Peek RM Jr. Helicobacter pylori: gastric cancer and beyond . Nat Rev Cancer 2010 ; 10 : 403 – 14 . Google Scholar CrossRef Search ADS PubMed 31 Milman N , Rosenstock S , Andersen L et al. Serum ferritin, hemoglobin, and Helicobacter pylori infection: a seroepidemiologic survey comprising 2794 Danish adults . Gastroenterology 1998 ; 115 : 268 – 74 . Google Scholar CrossRef Search ADS PubMed 32 Peach HG , Bath NE , Farish SJ. Helicobacter pylori infection: an added stressor on iron status of women in the community . Med J Aust 1998 ; 169 : 188 – 90 . Google Scholar PubMed 33 Berg G , Bode G , Blettner M et al. Helicobacter pylori infection and serum ferritin: A population-based study among 1806 adults in Germany . Am J Gastroenterol 2001 ; 96 : 1014 – 8 . Google Scholar CrossRef Search ADS PubMed 34 Parkinson AJ , Gold BD , Bulkow L et al. High prevalence of Helicobacter pylori in the Alaska native population and association with low serum ferritin levels in young adults . Clin Diagn Lab Immunol 2000 ; 7 : 885 – 8 . Google Scholar PubMed 35 Kaffes A , Cullen J , Mitchell H et al. Effect of Helicobacter pylori infection and low-dose aspirin use on iron stores in the elderly . J Gastroentero Hepatol 2003 ; 18 : 1024 – 8 . Google Scholar CrossRef Search ADS 36 Choe YH , Kim SK , Hong YC. Helicobacter pylori infection with iron deficiency anaemia and subnormal growth at puberty . Arch Dis Child 2000 ; 82 : 136 – 40 . Google Scholar CrossRef Search ADS PubMed 37 Christofides A , Schauer C , Zlotkin SH. Iron deficiency and anemia prevalence and associated etiologic risk factors in First Nations and Inuit communities in Northern Ontario and Nunavut . Can J Public Health 2005 ; 96 : 304 – 7 . Google Scholar PubMed 38 Seo JK , Ko JS , Choi KD. Serum ferritin and Helicobacter pylori infection in children: a sero-epidemiologic study in Korea . J Gastroenterol Hepatol 2002 ; 17 : 754 – 7 . Google Scholar CrossRef Search ADS PubMed 39 Weyermann M , Rothenbacher D , Gayer L et al. Role of Helicobacter pylori infection in iron deficiency during pregnancy . Am J Obstet Gynecol 2005 ; 192 : 548 – 53 . Google Scholar CrossRef Search ADS PubMed 40 Yang YJ , Sheu BS , Lee SC et al. Children of Helicobacter pylori-infected dyspeptic mothers are predisposed to H. pylori acquisition with subsequent iron deficiency and growth retardation . Helicobacter 2005 ; 10 : 249 – 55 . Google Scholar CrossRef Search ADS PubMed 41 Choe YH , Kwon YS , Jung MK et al. Helicobacter pylori-associated iron-deficiency anemia in adolescent female athletes . J Pediatr 2010 ; 139 : 100 – 4 . Google Scholar CrossRef Search ADS 42 Hershko C , Hoffbrand AV , Keret D et al. Role of autoimmune gastritis, Helicobacter pylori and celiac disease in refractory or unexplained iron deficiency anemia . Haematologica 2005 ; 90 : 585 – 95 . Google Scholar PubMed © The Author(s) 2018. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-Sen University This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Gastroenterology Report Oxford University Press

Unexplained iron deficiency anemia: does Helicobacter pylori have a role to play?

Loading next page...
 
/lp/ou_press/unexplained-iron-deficiency-anemia-does-helicobacter-pylori-have-a-am1ZUjTHGd
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-Sen University
eISSN
2052-0034
D.O.I.
10.1093/gastro/goy001
Publisher site
See Article on Publisher Site

Abstract

Abstract Background and aim Testing for Helicobacter pylori (Hp) infection is recommended for work-up of unexplained iron deficiency anemia (IDA), although the evidence supporting this recommendation is scant. The aim of this study was to investigate the association between Hp infection and unexplained iron deficiency (ID) or IDA in the older adult population without significant upper gastrointestinal source of blood loss. Methods Retrospective single-center cohort study; 523 out of 1253 consecutive patients who underwent esophagogastroduodenoscopy with no significant upper and/or lower gastrointestinal source for blood loss or risk factors for IDA. Comparisons were made between the Hp-positive and Hp-negative groups using Fisher exact test, chi-square test and Student’s t-test. Univariate and multiple logistic regression analyses were used to identify significant risk factors associated with ID and IDA. Results One hundred and three subjects (19.7%) had Hp infection and 420 (80.3%) were negative for Hp. Sixty-eight (22.1%) out of 307 subjects with available serum iron profile had unexplained ID and 28 (5.4%) out of 510 subjects with available hemoglobin profile had unexplained IDA. No association was found between ID/IDA and Hp infection in univariate and multiple logistic regression analyses. Conclusion We found no association between unexplained ID or IDA and Hp infection in older adult population without peptic ulcer disease or significant upper gastrointestinal source of blood loss. Helicobacter pylori, anemia, iron deficiency Introduction Helicobacter pylori (Hp) is the most common chronic bacterial infection in humans [1,2]. Iron deficiency anemia (IDA) is also a common condition with a prevalence of 1–2% of the adult population in the USA [3] and up to 16.6% in older adults [4]. More recent reports suggest a variable and higher prevalence of anemia in older adults, ranging between 2.9% and 61%, depending on the population studied and definition of anemia [5]. The major cause of iron deficiency (ID) in developed countries is overt or occult gastrointestinal blood loss [6]. Existing practice guidelines support the practice of performing upper and lower gastrointestinal endoscopic evaluation in patients with IDA and wireless video capsule endoscopy in those with unrevealing bidirectional endoscopic evaluation [7]. Despite these diagnostic modalities, the etiology of obscure gastrointestinal bleeding may remain elusive in approximately 30% of the patients [8]. Peptic ulcer disease caused by Hp infection can lead to gastrointestinal blood loss and IDA. Whether Hp infection can lead to IDA in the absence of peptic ulcer disease is controversial. Most of the data supporting association of Hp infection and IDA come from clinical studies conducted in children and pre-menopausal women with a relatively high iron requirement [9–11] and in those living in areas with a high prevalence for Hp infection [12]. The majority of the epidemiological studies that support this association have used serologic tests that do not necessarily diagnose active Hp infection. In addition, most of these studies have not ruled out the major causes of IDA such as peptic ulcer disease by esophagogastroduodenoscopy (EGD) [13]. Thus, the applicability of the available study findings in adult population living in areas with low prevalence for Hp infection who are not vulnerable to ID is controversial. The available data supporting association between Hp infection and ID do not prove cause and effect [14]. Nevertheless, the Maastricht IV Consensus on the management of Hp infection recommends testing and treatment for Hp infection in patients with unexplained IDA [15]. Hence our study was performed to evaluate the association between Hp infection and unexplained IDA in adult patients without obvious risk factors for ID living in areas with low prevalence for Hp infection. Methods Patients The study involved collection of Hp infection data on 1253 consecutive patients undergoing diagnostic or therapeutic upper gastrointestinal endoscopy at the Veterans Affairs Medical Center, Syracuse, from 1 January 1998 to 28 April 2004. All patients underwent EGD with Hp testing by standard biopsy protocol (two antral and two gastric body biopsies) as part of a previous Institutional Review Board-approved study investigating new diagnostic tests and treatment protocols for Hp infection [16,17]. One biopsy each from the antrum and body was sent for histology and rapid urease testing/Campylobacter-like organism (CLO) test. A subgroup of these patients (from 1 January 1998 to 31 December 1999) had consented to collection and storage of fasting serum samples prior to endoscopy. Serum iron tests were performed on these samples. A review of medical records was performed in all the subjects to determine the presence of ID/IDA. Medical, laboratory and pharmacy electronic records from 6 months before to 6 months after the performance of the endoscopy were reviewed. Demographic and clinical data included history of medical conditions known to cause ID, obvious causes for acute and/or chronic blood loss or impaired iron absorption, prior gastrointestinal surgery, alcohol or drug abuse, prescription/over-the-counter medication use (non-steroidal anti-inflammatory, proton pump inhibitor, iron supplementation, anticoagulant and antiplatelet medications), pertinent laboratory results, endoscopy and pathology reports. Patients with significant source of chronic and/or acute gastrointestinal blood loss identified on upper endoscopy and/or lower endoscopy [18,19], abnormal small bowel biopsies, clinical diagnosis consistent with celiac disease or other malabsorption syndromes, obvious cause of non-GI blood loss such as epistaxis or heavy menstrual bleed, previous treatment for Hp, indeterminate Hp status, ongoing iron therapy and insufficient clinical data were excluded. Determination of Hp status Hp status was determined by CLO test and presence of Hp organisms on histological evaluation of gastric biopsies. Positive Hp status was defined as positive CLO test and presence of Hp on histology. Negative Hp status was defined as negative CLO test and absence of Hp on histology. In patients with discordant results by CLO and histology, positive Hp serology or presence of chronic active gastritis on biopsy was used to determine the presence of active Hp infection. Patients with discordant CLO/histology results, who were on proton pump inhibitors (PPIs) and had no serology tests were deemed indeterminate. Determination of ID and IDA Blood hemoglobin level of <13 and <12 g/dL in men and women respectively was used to define anemia [20]. Patients were considered iron-deficient if serum ferritin level was <41 ng/mL. Prior studies conducted in anemic patients have shown that a cutoff serum ferritin level of 41 ng/mL has a sensitivity and specificity of 98% [21,22]. In those with anemia, we also used a higher cutoff ferritin level of 100 ng/mL [23] to ensure capture of ID in those with potentially coexistent anemia of chronic disease. Statistical analysis Demographic data, clinical characteristics and laboratory parameters including serum iron results were compared in the Hp-positive and Hp-negative groups. Fisher exact test or chi-square test was employed for analysis of categorical variables and Student’s t-test was used for analysis of continuous variables. A probability value of <0.05 was considered statistically significant. Similar univariate analysis of demographic data, clinical characteristics, Hp status and medication use [non-steroidal anti-inflammatory drugs (NSAIDs) and PPIs] was also performed in the groups with ID and IDA. Multiple logistic regression analysis was then performed using variables that were statistically significant on univariate analysis in the groups with ID and IDA. Results A total of 1253 consecutive patients who underwent EGD and standard testing for Hp infection from 1 January 1998 to 28 April 2004 were eligible for inclusion in the study. Seven hundred and 30 patients were excluded [endoscopic identification of a significant gastrointestinal bleeding source (n = 557), other causes for ID including celiac disease (n=60), inadequate data (n=74), previous treatment for Hp (n=27) and indeterminate Hp infection status (n=12)]. The final study population consisted of 523 subjects, of whom 488 (93.3%) were males and 35 (6.7%) were females. All the patients underwent EGD and 72% (n=378) underwent flexible sigmoidoscopy or colonoscopy. Out of the 523 subjects, 103 had Hp infection (19.7%) and 420 were negative for Hp (80.3%) (Table 1). The female patients were relatively younger as compared to the males (mean age 51.9 vs 61.8 years, data not shown). Age, gender, race, mean ferritin level, hemoglobin level or ID was not associated with Hp infection. Table 1. Comparison of variables in 523 patients with and without Helicobacter pylori (Hp) infection Hp-positive (n=103) Hp-negative (n=420) p-value Odds ratio 95% confidence interval Gender 0.66 0.82 0.36–1.85  Male 95 (19.5) 393 (80.5)  Female 8 (22.9) 27 (77.1) Race 0.24  Caucasian 93 (19.0) 396 (81.0)  African American 14 (63.6)  Others 2 (16.7) 10 (83.3) Age, years 61.7 ± 11.7 61.0 ± 13.1 0.62 Hemoglobin, g/dL 14.3 ± 1.8 (n=102) 14.1 ± 1.9 (n=408) 0.27 Ferritin, ng/mL 174.1 ± 215.0 (n=71) 185.1 ± 251.6 (n=236) 0.74 Iron deficiency 12 (17.6) 56 (82.4) 0.26 0.65 0.33–1.30 Hp-positive (n=103) Hp-negative (n=420) p-value Odds ratio 95% confidence interval Gender 0.66 0.82 0.36–1.85  Male 95 (19.5) 393 (80.5)  Female 8 (22.9) 27 (77.1) Race 0.24  Caucasian 93 (19.0) 396 (81.0)  African American 14 (63.6)  Others 2 (16.7) 10 (83.3) Age, years 61.7 ± 11.7 61.0 ± 13.1 0.62 Hemoglobin, g/dL 14.3 ± 1.8 (n=102) 14.1 ± 1.9 (n=408) 0.27 Ferritin, ng/mL 174.1 ± 215.0 (n=71) 185.1 ± 251.6 (n=236) 0.74 Iron deficiency 12 (17.6) 56 (82.4) 0.26 0.65 0.33–1.30 Data are presented as mean ± standard deviation or number (percentage). Table 1. Comparison of variables in 523 patients with and without Helicobacter pylori (Hp) infection Hp-positive (n=103) Hp-negative (n=420) p-value Odds ratio 95% confidence interval Gender 0.66 0.82 0.36–1.85  Male 95 (19.5) 393 (80.5)  Female 8 (22.9) 27 (77.1) Race 0.24  Caucasian 93 (19.0) 396 (81.0)  African American 14 (63.6)  Others 2 (16.7) 10 (83.3) Age, years 61.7 ± 11.7 61.0 ± 13.1 0.62 Hemoglobin, g/dL 14.3 ± 1.8 (n=102) 14.1 ± 1.9 (n=408) 0.27 Ferritin, ng/mL 174.1 ± 215.0 (n=71) 185.1 ± 251.6 (n=236) 0.74 Iron deficiency 12 (17.6) 56 (82.4) 0.26 0.65 0.33–1.30 Hp-positive (n=103) Hp-negative (n=420) p-value Odds ratio 95% confidence interval Gender 0.66 0.82 0.36–1.85  Male 95 (19.5) 393 (80.5)  Female 8 (22.9) 27 (77.1) Race 0.24  Caucasian 93 (19.0) 396 (81.0)  African American 14 (63.6)  Others 2 (16.7) 10 (83.3) Age, years 61.7 ± 11.7 61.0 ± 13.1 0.62 Hemoglobin, g/dL 14.3 ± 1.8 (n=102) 14.1 ± 1.9 (n=408) 0.27 Ferritin, ng/mL 174.1 ± 215.0 (n=71) 185.1 ± 251.6 (n=236) 0.74 Iron deficiency 12 (17.6) 56 (82.4) 0.26 0.65 0.33–1.30 Data are presented as mean ± standard deviation or number (percentage). Out of the 307 subjects with available serum ferritin results, 68 subjects (22.1%) were iron-deficient and 239 subjects had no ID (Table 2). Female gender was significantly associated with ID on univariate as well as multiple regression analysis (48% vs 20%, p = 0.004). Other variables such as Hp infection, age, gender, race, PPI use or NSAID use were not associated with ID. Table 2. Comparison of variables in patients with and without iron deficiency (serum ferritin results available in 307 patients) ID-positive (n=68) ID-negative (n=239) p-value Odds ratio 95% confidence interval Hp infection 12 (16.9) 59 (83.1) 0.26 0.65 0.33–1.30 Gender 0.004 0.27 0.12–0.62  Male 56 (19.9) 226 (80.1)  Female 12 (48.0) 13 (52.0) Race 0.48  Caucasian 65 (23) 218 (77)  African American 3 (18.8) 13 (81.2)  Others 0 (0.0) 8 (100.0) NSAID use 36 (22.2) 126 (77.8) 0.99 1.01 0.59–1.75 PPI use 27 (20.3) 106 (79.7) 0.58 0.83 0.48–1.43 Age, years 62.3 ± 12.7 61.9 ± 13.2 0.81 ID-positive (n=68) ID-negative (n=239) p-value Odds ratio 95% confidence interval Hp infection 12 (16.9) 59 (83.1) 0.26 0.65 0.33–1.30 Gender 0.004 0.27 0.12–0.62  Male 56 (19.9) 226 (80.1)  Female 12 (48.0) 13 (52.0) Race 0.48  Caucasian 65 (23) 218 (77)  African American 3 (18.8) 13 (81.2)  Others 0 (0.0) 8 (100.0) NSAID use 36 (22.2) 126 (77.8) 0.99 1.01 0.59–1.75 PPI use 27 (20.3) 106 (79.7) 0.58 0.83 0.48–1.43 Age, years 62.3 ± 12.7 61.9 ± 13.2 0.81 Data are presented as mean ± standard deviation or number (percentage). ID, iron deficiency; Hp, Helicobacter pylori; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor. Table 2. Comparison of variables in patients with and without iron deficiency (serum ferritin results available in 307 patients) ID-positive (n=68) ID-negative (n=239) p-value Odds ratio 95% confidence interval Hp infection 12 (16.9) 59 (83.1) 0.26 0.65 0.33–1.30 Gender 0.004 0.27 0.12–0.62  Male 56 (19.9) 226 (80.1)  Female 12 (48.0) 13 (52.0) Race 0.48  Caucasian 65 (23) 218 (77)  African American 3 (18.8) 13 (81.2)  Others 0 (0.0) 8 (100.0) NSAID use 36 (22.2) 126 (77.8) 0.99 1.01 0.59–1.75 PPI use 27 (20.3) 106 (79.7) 0.58 0.83 0.48–1.43 Age, years 62.3 ± 12.7 61.9 ± 13.2 0.81 ID-positive (n=68) ID-negative (n=239) p-value Odds ratio 95% confidence interval Hp infection 12 (16.9) 59 (83.1) 0.26 0.65 0.33–1.30 Gender 0.004 0.27 0.12–0.62  Male 56 (19.9) 226 (80.1)  Female 12 (48.0) 13 (52.0) Race 0.48  Caucasian 65 (23) 218 (77)  African American 3 (18.8) 13 (81.2)  Others 0 (0.0) 8 (100.0) NSAID use 36 (22.2) 126 (77.8) 0.99 1.01 0.59–1.75 PPI use 27 (20.3) 106 (79.7) 0.58 0.83 0.48–1.43 Age, years 62.3 ± 12.7 61.9 ± 13.2 0.81 Data are presented as mean ± standard deviation or number (percentage). ID, iron deficiency; Hp, Helicobacter pylori; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor. Out of the total of 523 subjects, 510 subjects had hemoglobin levels available and they were classified as anemic and not anemic. IDA was present in 28 (5.4%) with available ferritin results, when a cutoff of <41 ng/mL was used for serum ferritin level to define ID (Table 3). Using a higher cutoff for serum ferritin level of <100 ng/mL in those with anemia, IDA was present in only 46 subjects (9.0%). No significant association between IDA and Hp infection was found even with using a higher cutoff for serum ferritin level of <100 ng/mL in those with anemia (data not shown). However, the patients in this subgroup with IDA and higher serum ferritin cutoff were found to be significantly older compared to those without IDA (mean age, 66.04 vs 60.71 years, p < 0.01) (data not shown). Table 3. Comparison of variables in patients with and without iron deficiency anemia (hemoglobin levels available in only 510 patients) IDA-positive (n=28) IDA-negative (n=482) p-value Odds ratio 95% confidence interval Hp infection 4 (3.9) 98 (96.1) 0.63 0.65 0.22–1.93 Gender 0.43 0.59 0.17–2.07  Male 25 (5.3) 450 (94.7)  Female 3 (8.6) 32 (91.4) Race 0.76  Caucasian 26 (5.5) 450 (94.5)  African American 2 (9.1) 20 (90.9)  Others 0 (0.0) 11 (100.0) NSAID use 15 (5.7) 250 (94.3) 0.84 1.12 0.51–2.44 PPI use 11 (4.4) 239 (95.6) 0.33 0.66 0.30–1.43 Age, years 65.4 ± 12.2 61 ± 12.8 0.07 IDA-positive (n=28) IDA-negative (n=482) p-value Odds ratio 95% confidence interval Hp infection 4 (3.9) 98 (96.1) 0.63 0.65 0.22–1.93 Gender 0.43 0.59 0.17–2.07  Male 25 (5.3) 450 (94.7)  Female 3 (8.6) 32 (91.4) Race 0.76  Caucasian 26 (5.5) 450 (94.5)  African American 2 (9.1) 20 (90.9)  Others 0 (0.0) 11 (100.0) NSAID use 15 (5.7) 250 (94.3) 0.84 1.12 0.51–2.44 PPI use 11 (4.4) 239 (95.6) 0.33 0.66 0.30–1.43 Age, years 65.4 ± 12.2 61 ± 12.8 0.07 Data are presented as mean ± standard deviation or number (percentage). IDA, iron deficiency anemia; Hp, Helicobacter pylori; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor. Table 3. Comparison of variables in patients with and without iron deficiency anemia (hemoglobin levels available in only 510 patients) IDA-positive (n=28) IDA-negative (n=482) p-value Odds ratio 95% confidence interval Hp infection 4 (3.9) 98 (96.1) 0.63 0.65 0.22–1.93 Gender 0.43 0.59 0.17–2.07  Male 25 (5.3) 450 (94.7)  Female 3 (8.6) 32 (91.4) Race 0.76  Caucasian 26 (5.5) 450 (94.5)  African American 2 (9.1) 20 (90.9)  Others 0 (0.0) 11 (100.0) NSAID use 15 (5.7) 250 (94.3) 0.84 1.12 0.51–2.44 PPI use 11 (4.4) 239 (95.6) 0.33 0.66 0.30–1.43 Age, years 65.4 ± 12.2 61 ± 12.8 0.07 IDA-positive (n=28) IDA-negative (n=482) p-value Odds ratio 95% confidence interval Hp infection 4 (3.9) 98 (96.1) 0.63 0.65 0.22–1.93 Gender 0.43 0.59 0.17–2.07  Male 25 (5.3) 450 (94.7)  Female 3 (8.6) 32 (91.4) Race 0.76  Caucasian 26 (5.5) 450 (94.5)  African American 2 (9.1) 20 (90.9)  Others 0 (0.0) 11 (100.0) NSAID use 15 (5.7) 250 (94.3) 0.84 1.12 0.51–2.44 PPI use 11 (4.4) 239 (95.6) 0.33 0.66 0.30–1.43 Age, years 65.4 ± 12.2 61 ± 12.8 0.07 Data are presented as mean ± standard deviation or number (percentage). IDA, iron deficiency anemia; Hp, Helicobacter pylori; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor. Logistic regression analysis showed female gender to be the only significant factor associated with ID (Table 4). The significance of gender however did not hold true in those with IDA on univariate or multivariate analysis (data not shown). Table 4. Logistic regression model in subjects with iron deficiency p-value Odds ratio 95% confidence interval Age (years) 0.57 1.01 0.98–1.03 Hp infection (positive vs negative) 0.16 0.59 0.28–1.23 Gender (male vs female) <0.001 0.21 0.09–0.52 Race (Caucasian vs others) 0.20 2.34 0.63–8.64 NSAID Uses (yes vs no) 0.59 1.17 0.66–2.08 PPI use (yes vs no) 0.47 0.81 0.45–1.45 p-value Odds ratio 95% confidence interval Age (years) 0.57 1.01 0.98–1.03 Hp infection (positive vs negative) 0.16 0.59 0.28–1.23 Gender (male vs female) <0.001 0.21 0.09–0.52 Race (Caucasian vs others) 0.20 2.34 0.63–8.64 NSAID Uses (yes vs no) 0.59 1.17 0.66–2.08 PPI use (yes vs no) 0.47 0.81 0.45–1.45 Hp, Helicobacter pylori; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor. Table 4. Logistic regression model in subjects with iron deficiency p-value Odds ratio 95% confidence interval Age (years) 0.57 1.01 0.98–1.03 Hp infection (positive vs negative) 0.16 0.59 0.28–1.23 Gender (male vs female) <0.001 0.21 0.09–0.52 Race (Caucasian vs others) 0.20 2.34 0.63–8.64 NSAID Uses (yes vs no) 0.59 1.17 0.66–2.08 PPI use (yes vs no) 0.47 0.81 0.45–1.45 p-value Odds ratio 95% confidence interval Age (years) 0.57 1.01 0.98–1.03 Hp infection (positive vs negative) 0.16 0.59 0.28–1.23 Gender (male vs female) <0.001 0.21 0.09–0.52 Race (Caucasian vs others) 0.20 2.34 0.63–8.64 NSAID Uses (yes vs no) 0.59 1.17 0.66–2.08 PPI use (yes vs no) 0.47 0.81 0.45–1.45 Hp, Helicobacter pylori; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor. Discussion Our study did not show an association between ID/IDA and Hp infection in adult population, using strict (ferritin level of <41ng/mL) and liberal (ferritin level of <100 ng/mL) criteria to define ID/IDA. This lack of association may be attributed to the low vulnerability of our patients to ID/IDA (predominantly adult males with no increased risk for ID living in areas with low prevalence for Hp infection) as well as the exclusion of upper and/or lower gastrointestinal source of blood loss and confirmation of the presence of active Hp infection. The prevalence of Hp infection in our study population was 19.7% compared to 30.1–39.5% in other epidemiologic studies performed in the USA [13]. This lower prevalence is likely explained by the use of serology for detecting Hp infection in the above studies and the exclusion of patients with indeterminate Hp infection status, previous treatment for Hp infection, and upper and/or lower gastrointestinal source of blood loss in our study. Although female gender was the only significant factor associated with ID in multiple logistic regression, there was no significant difference in the Hp infection status in females with and without ID. However, the small number of female patients in our study (6.7%) limits further interpretation. The mechanisms by which Hp infection is postulated to cause IDA are Hp-associated chronic gastritis resulting in hypo- or achlorhydria, reduced ascorbic acid secretion and reduced intestinal iron absorption, occult blood loss due to chronic erosive gastritis, and sequestration and utilization of iron by Hp [24]. The major studies that have reported Hp infection to be an independent risk factor for IDA in North America were conducted in school-aged children residing in rural Alaska with a high prevalence of Hp infection and IDA [12] and in participants of the National Health and Nutrition Examination Survey in whom serologic tests were used for diagnosis of Hp infection [13]. Other studies that suggested a role for Hp eradication in improving IDA were conducted in children, adolescents and pre-menopausal women who have a relatively high iron requirement to meet the demands of growth and menstrual blood loss [9–11]. On the other hand, there are epidemiologic studies that showed no association between Hp seropositivity and ID/IDA [25–29]. In summary, the causal relationship between Hp infection and ID/IDA remains controversial. Our study did not show any association between Hp infection and ID/IDA. The Maastricht IV Consensus on the management of Hp infection recommends testing and treatment of Hp infection in patients with unexplained IDA [15]. Although these guidelines may be applicable in countries with high prevalence for Hp infection, the universal adoption of this guideline in areas with low prevalence for Hp infection such as the USA may result in unnecessary testing and treatment. More importantly, this practice could delay the diagnosis of other serious conditions that could cause ID/IDA in older population. The evidence that carriage of certain Hp strains is inversely related to the prevalence of Barrett’s esophagus, esophageal adenocarcinoma, asthma and atopic disorders has prompted some authors to warn against testing and treating for Hp infection in asymptomatic individuals [30]. While we concur with the current guidelines that, if testing for Hp infection is undertaken, appropriate treatment and confirmation of eradication of the infection should be ensured in all patients with positive test result for Hp infection, our study results do not support the recommendation that testing for Hp infection should be performed in all patients with unexplained IDA. The strengths of our study include the identification and exclusion of significant upper gastrointestinal source of blood loss via EGD in all the subjects, the adoption of strict criteria to determine active Hp infection and the use of a higher cutoff for serum ferritin to capture those with potential ID. In most of the observational epidemiologic studies evaluating association between Hp infection and ID, EGD was not performed [12,13,25–27,31–40]. We used a combination of CLO testing and detection of Hp on histology to adjudicate Hp status, which provides a more accurate determination of the Hp infection status. The majority of previous studies looking at association of Hp and IDA used serology for identification of Hp infection [13,26,27,31–38]. Only a few studies used tests besides serology to determine active Hp infection [12,39–42]. However, these studies were conducted in subjects vulnerable to ID such as children and adolescent females living in areas with a high prevalence for Hp infection. The limitations of our study include the retrospective study design, the study population comprising predominantly adult males who are typically not vulnerable to ID and the availability of lower gastrointestinal endoscopy results in only 72% of the study population. The selection of a homogenous patient population without the confounding effects of vulnerability to ID is, however, a better model to study the association between Hp infection and IDA. Although the study was retrospective in nature, a large number of our patients had biopsies for Hp performed by protocol and serum samples collected for calculation of serum iron indices prospectively at the time of EGD. While the availability of lower gastrointestinal endoscopy results on all patients would have been ideal, bidirectional endoscopy as well as appropriate small bowel imaging studies was conducted in all the patients who presented with overt or occult gastrointestinal blood loss. Additionally, all patients with a significant source of chronic and/or acute gastrointestinal blood loss identified on endoscopic or small bowel imaging tests were excluded from the study. It is to be also noted that prior studies showing association between unexplained ID and Hp infection did not have strict exclusion criteria as are used in our study and did not have upper and lower gastrointestinal endoscopy data on all patients. In conclusion, we found no association between ID or IDA and Hp infection in older adult population without peptic ulcer disease or significant upper gastrointestinal source of blood loss. Our study does not support routine testing for Hp infection in adult patients with unexplained IDA living in areas with low prevalence for Hp infection. More importantly, work-up of IDA, particularly in patients above 60 years of age, should not end with the diagnosis of Hp infection, as such a practice could lead to delayed diagnosis of potentially more serious underlying pathology. Conflict of interest statement: none declared. References 1 Cave DR. Transmission and epidemiology of Helicobacter pylori . Am J Med 1996 ; 100(Suppl 5A) : 12S – 18S . Google Scholar CrossRef Search ADS 2 Pounder RE , Ng D. The prevalence of Helicobacter pylori infection in different countries . Aliment Pharmacol Ther 1995 ; 9(Suppl 2) : 33 – 9 . Google Scholar PubMed 3 Looker AC , Dallman PR , Carroll MD et al. Prevalence of iron deficiency in the United States . JAMA 1997 ; 277 : 973 – 6 . Google Scholar CrossRef Search ADS PubMed 4 Guralnik JM , Eisenstaedt RS , Ferrucci L et al. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia . Blood 2004 ; 104 : 2263 – 8 . Google Scholar CrossRef Search ADS PubMed 5 Beghe C, , Wilson A , Ershler WB. Prevalence and outcomes of anemia in geriatrics: a systematic review of the literature . Am J Med 2004 ; 116(Suppl 7A) : 3S – 10S . Google Scholar CrossRef Search ADS PubMed 6 Cook JD , Skikne BS. Iron deficiency: definition and diagnosis . J Intern Med 1989 ; 226 : 349 – 55 . Google Scholar CrossRef Search ADS PubMed 7 Raju GS , Gerson L , Das A et al. ; American Gastroenterological Association. American Gastroenterological Association (AGA) Institute technical review on obscure gastrointestinal bleeding . Gastroenterology 2007 ; 133 : 1697 – 717 . Google Scholar CrossRef Search ADS PubMed 8 Szold A , Katz LB , Lewis BS. Surgical approach to occult gastrointestinal bleeding . Am J Surg 1992 ; 163 : 90 – 3 . Google Scholar CrossRef Search ADS PubMed 9 Annibale B , Marignani M , Monarca B et al. Reversal of iron deficiency anemia after Helicobacter pylori eradication in patients with asymptomatic gastritis . Ann Intern Med 1999 ; 131 : 668 – 72 . Google Scholar CrossRef Search ADS PubMed 10 Choe YH , Kim SK , Son BK et al. Randomized placebo-controlled trial of Helicobacter pylori eradication for iron-deficiency anemia in preadolescent children and adolescents . Helicobacter 1999 ; 4 : 135 – 9 . Google Scholar CrossRef Search ADS PubMed 11 Hacihanefioglu A , Edebali F , Celebi A et al. Improvement of complete blood count in patients with iron deficiency anemia and Helicobacter pylori infection after the eradication of Helicobacter pylori . Hepatogastroenterology 2004 ; 51 : 313 – 5 . Google Scholar PubMed 12 Baggett HC , Parkinson AJ , Muth PT et al. Endemic iron deficiency associated with Helicobacter pylori infection among school-aged children in Alaska . Pediatrics 2006 ; 117 : e396 – 404 . Google Scholar CrossRef Search ADS PubMed 13 Cardenas VM , Mulla ZD , Ortiz M et al. Iron deficiency and Helicobacter pylori infection in the United States . Am J Epidemiol 2006 ; 163 : 127 – 34 . Google Scholar CrossRef Search ADS PubMed 14 Chey WD , Wong BC ; Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection . Am J Gastroenterol 2007 ; 102 : 1808 – 25 . Google Scholar CrossRef Search ADS PubMed 15 Malfertheiner P , Megraud F , O’Morain CA et al. Management of Helicobacter pylori infection—the Maastricht IV/ Florence Consensus Report . Gut 2012 ; 61 : 646 – 64 . Google Scholar CrossRef Search ADS PubMed 16 Ahmed F , Murthy UK , Chey WD et al. Evaluation of the Ez-HBT Helicobacter blood test to establish Helicobacter pylori eradication . Aliment Pharmacol Ther 2005 ; 22 : 875 – 80 . Google Scholar CrossRef Search ADS PubMed 17 Chey WD , Murthy U , Toskes P et al. The 13C-urea blood test accurately detects active Helicobacter pylori infection: a United States, multicenter trial . Am J Gastroenterol 1999 ; 94 : 1522 – 4 . Google Scholar CrossRef Search ADS PubMed 18 Rockey DC , Cello JP. Evaluation of the gastrointestinal tract in patients with iron-deficiency anemia . N Engl J Med 1993 ; 329 : 1691 – 5 . Google Scholar CrossRef Search ADS PubMed 19 Zuckerman GR , Prakash C , Askin MP et al. AGA technical review on the evaluation and management of occult and obscure gastrointestinal bleeding . Gastroenterology 2000 ; 118 : 201 – 21 . Google Scholar CrossRef Search ADS PubMed 20 Nutritional anaemias . Report of a WHO scientific group . World Health Organ Tech Rep Ser 1968 ; 405 : 5 – 37 . PubMed 21 Mast AE , Blinder MA , Gronowski AM et al. Clinical utility of the soluble transferrin receptor and comparison with serum ferritin in several populations . Clin Chem 1998 ; 44 : 45 – 51 . Google Scholar PubMed 22 Punnonen K , Irjala K , Rajamaki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency . Blood 1997 ; 89 : 1052 – 7 . Google Scholar PubMed 23 Guyatt GH , Oxman AD , Ali M et al. Laboratory diagnosis of iron-deficiency anemia: an overview . J Gen Inten Med 1992 ; 7 : 145 – 53 . Google Scholar CrossRef Search ADS 24 DuBois S , Kearney DJ. Iron-deficiency anemia and Helicobacter pylori infection: a review of the evidence . Am J Gastroenterol 2005 ; 100 : 453 – 9 . Google Scholar CrossRef Search ADS PubMed 25 Collett JA , Burt MJ , Frampton CM et al. Seroprevalence of Helicobacter pylori in the adult population of Christchurch: risk factors and relationship to dyspeptic symptoms and iron studies . N Z Med J 1999 ; 112 : 292 – 5 . Google Scholar PubMed 26 Choi JW. Does Helicobacter pylori infection relate to iron deficiency anaemia in prepubescent children under 12 years of age? Acta Paediatr 2003 ; 92 : 970 – 2 . Google Scholar CrossRef Search ADS PubMed 27 Pilott A , Fabrello R , Franceschi M et al. Helicobacter pylori infection in asymptomatic elderly subjects living at home or in a nursing home: effects on gastric function and nutritional status . Age Ageing 1996 ; 25 : 245 – 9 . Google Scholar CrossRef Search ADS PubMed 28 Gessner BD , Baggett HC , Muth PT et al. A controlled, household-randomized, open-label trial of the effect that treatment of Helicobacter pylori infection has on iron deficiency in children in rural Alaska . J Infect Dis 2006 ; 193 : 537 – 46 . Google Scholar CrossRef Search ADS PubMed 29 Fagan RP , Dunaway CE , Bruden DL et al. Controlled, household-randomized, open-label trial of the effect of treatment of Helicobacter pylori infection on iron deficiency among children in rural Alaska: results at 40 months . J Infect Dis 2009 ; 199 : 652 – 60 . Google Scholar CrossRef Search ADS PubMed 30 Polk DB , Peek RM Jr. Helicobacter pylori: gastric cancer and beyond . Nat Rev Cancer 2010 ; 10 : 403 – 14 . Google Scholar CrossRef Search ADS PubMed 31 Milman N , Rosenstock S , Andersen L et al. Serum ferritin, hemoglobin, and Helicobacter pylori infection: a seroepidemiologic survey comprising 2794 Danish adults . Gastroenterology 1998 ; 115 : 268 – 74 . Google Scholar CrossRef Search ADS PubMed 32 Peach HG , Bath NE , Farish SJ. Helicobacter pylori infection: an added stressor on iron status of women in the community . Med J Aust 1998 ; 169 : 188 – 90 . Google Scholar PubMed 33 Berg G , Bode G , Blettner M et al. Helicobacter pylori infection and serum ferritin: A population-based study among 1806 adults in Germany . Am J Gastroenterol 2001 ; 96 : 1014 – 8 . Google Scholar CrossRef Search ADS PubMed 34 Parkinson AJ , Gold BD , Bulkow L et al. High prevalence of Helicobacter pylori in the Alaska native population and association with low serum ferritin levels in young adults . Clin Diagn Lab Immunol 2000 ; 7 : 885 – 8 . Google Scholar PubMed 35 Kaffes A , Cullen J , Mitchell H et al. Effect of Helicobacter pylori infection and low-dose aspirin use on iron stores in the elderly . J Gastroentero Hepatol 2003 ; 18 : 1024 – 8 . Google Scholar CrossRef Search ADS 36 Choe YH , Kim SK , Hong YC. Helicobacter pylori infection with iron deficiency anaemia and subnormal growth at puberty . Arch Dis Child 2000 ; 82 : 136 – 40 . Google Scholar CrossRef Search ADS PubMed 37 Christofides A , Schauer C , Zlotkin SH. Iron deficiency and anemia prevalence and associated etiologic risk factors in First Nations and Inuit communities in Northern Ontario and Nunavut . Can J Public Health 2005 ; 96 : 304 – 7 . Google Scholar PubMed 38 Seo JK , Ko JS , Choi KD. Serum ferritin and Helicobacter pylori infection in children: a sero-epidemiologic study in Korea . J Gastroenterol Hepatol 2002 ; 17 : 754 – 7 . Google Scholar CrossRef Search ADS PubMed 39 Weyermann M , Rothenbacher D , Gayer L et al. Role of Helicobacter pylori infection in iron deficiency during pregnancy . Am J Obstet Gynecol 2005 ; 192 : 548 – 53 . Google Scholar CrossRef Search ADS PubMed 40 Yang YJ , Sheu BS , Lee SC et al. Children of Helicobacter pylori-infected dyspeptic mothers are predisposed to H. pylori acquisition with subsequent iron deficiency and growth retardation . Helicobacter 2005 ; 10 : 249 – 55 . Google Scholar CrossRef Search ADS PubMed 41 Choe YH , Kwon YS , Jung MK et al. Helicobacter pylori-associated iron-deficiency anemia in adolescent female athletes . J Pediatr 2010 ; 139 : 100 – 4 . Google Scholar CrossRef Search ADS 42 Hershko C , Hoffbrand AV , Keret D et al. Role of autoimmune gastritis, Helicobacter pylori and celiac disease in refractory or unexplained iron deficiency anemia . Haematologica 2005 ; 90 : 585 – 95 . Google Scholar PubMed © The Author(s) 2018. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-Sen University This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Journal

Gastroenterology ReportOxford University Press

Published: Aug 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off